During the last decade new enabling technologies in molecular biology, chemistry, automation, and information technology have dramatically reshaped pharmaceutical and biological research. The completion of the sequencing of the genome in humans and mice has opened new opportunities to study the relationship between gene expression and behavioral function. Although the function of many genes is being unraveled resulting in many promising therapeutic targets, progress in understanding neuropsychiatric disorders is lacking.
In vivo behavioral biology is needed to validate behavioral phenotypes associated with newly discovered genes and new drug leads. As it is a slow, labor-intensive, high-maintenance technique it creates a bottleneck, and creates a need for a novel paradigm with a new approach to modern, scalable and automated technology.
Drug Discovery.
The development of new drugs and medications involves the study of their effects on various animals. The use of mice, dogs and other animals for experimental purposes is needed to obtain data so that subsequent tests on humans may be safely carried out.
Assessing behavior and the effects of drugs on laboratory animals has been a central component of the field of neuropharmacology. The discovery of chlorpromazine, for example, as a drug that produces differential effects on avoidance and escape behavior provided a strong impetus for evaluating the behavioral effects of experimental antipsychotic drugs. The growth of neuropharmacology coincided also with the development of the field of operant conditioning. Indeed, many of the techniques used to control and monitor operant behavior were enthusiastically endorsed by behavioral pharmacologists. It is recognized nowadays that the assessment of behavior in determining the effects of drugs is of pivotal importance.
Phenotype/Genotype Correlation.
With the completion of the genome sequence in both humans and mice, a wealth of information has inundated the scientific community. Thousands of genetically manipulated animals are being generated in hundreds of different laboratories for many different purposes. Although the research in academia and industry focusing on the function of genes is normally hypothesis driven, most of the time there are secondary adaptations (“side effects”) that confound or obliterate the targeted gene function. For example, a gene involved in memory may result in abnormal sensory function, and therefore many tests for the assessment of memory may have to be ruled out, if they depend on the sensory function affected. The difficulty is that laboratories that develop these genetically manipulated animals rarely have the capacity to test for secondary adaptations and most of these may go unnoticed.
In the area of functional genomics there is therefore a special need for a comprehensive assessment of behavior that brings the ability to correlate behavior, physiology and gene expression and allows to rule out secondary adaptations as the cause of observed behavioral and physiological phenotypes.
Standard Behavioral Techniques
Although great progress has been made in the development of techniques that permit objective and quantitative study of behavior, these techniques involve considerable expertise and effort. In the field of neuropharmacology, for example, the adoption and widespread use of these procedures has had the multiple benefit of broadening our understanding of the principles governing behavior, elucidating the mechanisms of drug action, and demonstrating the complex neurochemical substrates influencing both behavior and drug action. However, these behavioral techniques are time consuming, they provide a limited picture of the animal's behavior and do not allow a comprehensive assessment of the test subject. The type of behavioral assessment currently used is limited by the choice of the end point measures or dependent variables, and by the limitation of the observation to a given period. Behavioral data are therefore limited to and by what the scientific community considers a relevant variable, by the way this variable is measured, and by the context and time constraints of the testing.
Behavioral data are collected using a myriad of different techniques. In some cases, drug-induced behavior is assessed by trained observers who employ rating scales. Although a trained observer can detect complex and/or subtle changes in behavior, there is an intrinsic variability and subjectivity in the behavioral data generated in this way. Reliability of the data heavily depends on the expertise of the observer. This method is obviously constrained by the short duration of the observation.
In drug research, for example, various devices are often used for measuring the activity of a test animal treated with an experimental substance. Normal activity of untreated animals is measured to provide a comparison with the results from treated animals. Measurements of activity are usually done with scientific equipment for continuously monitoring an animal's movement within a confined area. Whereas these devices permit prolonged observation of the animal's activity, other concurrent behaviors are normally ignored.
Various types of animal activity monitors have been used by behavioral analysts to study the effects induced upon the animal by experimental drugs. Such monitors include, for example, video equipment and light sensors. These types of monitors have been limiting in the study of animal behavior because they only allow the dimension the animal's visually detectable gross motion activities such as, for example, locomotion and stereotyped motor behavior. Complex behavioral assessment data is unavailable from these types of monitors.
An additional problem in the study of animal behavior using conventional methods is that the test subject is usually transported from the colony room to a test area or cage, in a different room, where the behavioral studies are conducted. This removal involves handling the test subject, placing it on a cart and rolling the cart away, and placing it in a different environment. This procedure by itself has profound influences on the animal's behavior thereby affecting the results. If processes related to stress, for example, are to be avoided, this movement of animals from one setting to another is clearly counterproductive.
Thus, in both the area of functional genomics and in drug discovery, there remains a need in the art for an apparatus and method that provides assessment of animal's behavior beyond mere gross motor activities. A comprehensive assessment over long or short periods of time is required. Such assessment can include what type of activity is performed, its intensity, frequency and duration, how these parameters change over time, and what complex patterns that involved a succession of different behaviors can be detected. A system that can link these measurements to telemetric devices measuring blood pressure, heart rate and other physiological parameters in parallel to the acquisition of behavioral data will be invaluable. In addition, there is a need to provide a method to reduce the level of manipulation of the test subject.